Study Shows Gene Therapy Benefits B Patients with Antibodies Against Virus Used to Carry Payload

Rare Daily Staff

A study that reanalyzed pre-treatment sera samples of the ten patients in the phase 1/2 clinical trial of UniQure’s hemophilia B gene therapy AMT-060 found that there was no relationship detected between the presence of pre-treatment antibodies targeting the AAV5 virus and outcomes of patients treated with the gene therapy carried by the AAV5 vector.

In ongoing gene therapy clinical trials using adeno-associated virus vectors, patients who present levels of anti-AAV neutralizing antibodies are excluded from treatment due to concern that the efficacy of AAV vector delivery may be negatively influenced by their presence. In this study, UniQure researchers explored the impact of anti-AAV5 neutralizing antibody levels on the efficacy of gene therapy delivery by an AAV5-based vector. UniQure presented the data in a session at the American Society of Gene and Cell Therapy Annual Meeting in Chicago, Illinois, the preeminent gene and cell therapy conference in the world.

“The study suggests that, in contrast to experience with other AAV vectors, detectable pre-existing neutralizing antibodies do not prevent successful gene transfer using AAV5 at clinical doses,” said Sander van Deventer, chief scientific officer of UniQure. “In patients pre-exposed to AAV5 who tested positive for anti-AAV5 antibodies, therapeutic transgene expression was established with no cellular immune response observed after systemic administration of AAV5.”

In the study, seven of the ten patients returned results below the limit of detection of the assay, and three of the ten had positive anti-AAV5 neutralizing antibody titers, of whom two were confirmed positive by additional assays. No relationship was determined between the presence of pre-treatment anti-AAV5 NABs and clinical outcomes in the trial.

The patient with the highest anti-AAV5 neutralizing antibody titer in the study presented the highest mean factor IX activity in his dose cohort. Neither of the two patients with confirmed positive anti-AAV5 NABs experienced elevated liver enzymes. Additionally, no clinically relevant T-cell immune responses to the capsid were detected in any of the ten patients.

The findings were further supported by a study in non-human primates that showed that anti-AAV5 neutralizing antibodies did not impair the efficacy of AMT-060 liver transduction.

“These findings suggest that AAV5-based gene therapies may be applicable to all, or nearly all, patients with hemophilia, Huntington’s disease, and other life-altering disorders,” said Matthew Kapusta, CEO of UniQure.

May 21, 2018
Photo: Matthew Kapusta, CEO of UniQure